Device for releasing with delayed effect an active substance, in particular veterinary

ABSTRACT

A device for dispensing an active substance to be used in a biological medium, in particular in the rumen of an animal, includes a sealed receptacle for containing the substance, and having at least one opening; a closure for provisionally closing the opening of the receptacle, the closure being maintained closed by at least one biodegradable element such that subsequent to the biological degradation of the element, the closure completely releases the opening.

This application is a 371 of PCT/FR97/01880 filed Oct. 20, 1997.

BACKGROUND OF THE INVENTION

The invention relates to a device for the delayed release of an activesubstance, especially a veterinary active substance.

DESCRIPTION OF THE RELATED ART

In the past fifteen years, much research has been carried out inveterinary pharmacy in order to optimize the release of medicinalproducts in domestic rearing animals or pets.

One of the main axes of research is directed towards developinganthelmintic compounds intended for the treatment of the verminoses ofruminants (bovines, goats, etc.).

As regards the oral route, the most common formulations involvemedicinal premixes or granules containing anthelmintic agents. Moresophisticated formulations have also been designed for the oral route.These allow release of the active principle over a longer period of timeand thereby avoid the need to regularly retreat the animals and to seekthem out in the pasture in order to administer treatment. These deviceswith sustained release of active principle (also known as intraruminaldiffusers or boli) allow release of the active principle by diffusionacross a matrix excipient by erosion of one of the componentsconstituting the device, by the action of an electronic system whichallows programmed release over time, or alternatively by osmoticpressure.

These devices are maintained in the rumen of the ruminants either bymeans of the density of the device or its specific geometry whichprevents regurgitation of the bolus during rumination.

However, on account of the constraints imposed by the size of the devicewhich needs to be administered and the daily amount of product whichneeds to be released in order to obtain a pharmacological effect, one ofthe major problems lies in the fact that the active principle isreleased over an insufficient period, 140-150 days at most, with theamount of active principle released not increasing during the season inpasture, or even decreasing over time.

In addition, another drawback is that the active principle isessentially released during the first months in pasture, when the fieldscontain a relatively low number of worms and eggs, while the digestivetract and the lungs of the animals contain few worms or larvae at thestart of the season in pasture. As a result, the animals generally showno infestation or any clinical signs due to verminoses during thisperiod.

Furthermore, the immediate release of the active principle when theanimals are placed in pasture at an early stage compromises the releaseof this active principle at a stage at which it would be necessary, i.e.in July and August.

Early release of the active principle also has the drawback of avoidingcontact between the host and the infesting agent at a stage when thiscontact would allow the ruminant to acquire immune protection againstthese parasites.

A need thus exists for a device which would, on the one hand, allow alag phase after ingestion of the device by the animal, before anyrelease of active principle at the moment when the animals are placed inpasture, and which would, on the other hand, ensure a release of anactive agent, in particular an anthelmintic agent, continuously orpreferably in waves, in an amount increasing as a function of timeduring the months of July and August.

SUMMARY OF THE INVENTION

So as to satisfy such a need, the subject of the invention is a devicefor distributing an active substance, this device being intended to beused in a biological medium, in particular the rumen of an animal,comprising:

a leakproof container intended to contain the said substance, the saidcontainer comprising at least one opening;

a means for temporary closure of the opening of the said container, thesaid closure means being held closed by at least one biodegradablecomponent, such that, after the said component has biodegraded, theclosure means completely frees the said opening.

In a first embodiment, the container is a flexible leakproof sachet or aleakproof sachet with a certain amount of rigidity and which can berolled up and unrolled. Any nonbiodegradable leakproof material may besuitable. Mention may be made of a nonbiodegradable polymer, inparticular a polypropylene, polyester, polyvinyl, etc.

The closure means advantageously includes a member formed of twocomponents which are applied one on top of the other.

These two components can be held together at each of their ends by thebiodegradable component. They can also be linked together by a portionforming a hinge and held together at only one end by the saidbiodegradable component.

These two components preferably comprise complementary longitudinalgrooves on their inner face, such that, when the two components areapplied one on top of the other, the grooves interlock and ensure thetotal leaktightness of the closure means.

The closure means advantageously comprises a clip, which is normallyopen, and is held closed by means of the biodegradable component, thesaid clip preferably having arms comprising interlocking grooves.

In a second embodiment, the container is formed of a rigid cup ofcylindrical shape, closed at one of its ends and open at its other end,and the means for temporary closure of the said open end comprises adisk pierced with a central orifice, a stopper whose shape matches thatof this central orifice and which is held on the said central orifice bythe biodegradable component supported by a ring, and by a collarintended to be fixed onto the cup in order to keep the disk and the ringapplied against the open end of the said cup.

In a third embodiment, the receptacle is formed of a cylinder comprisinga ballasting component at one of its ends and a stopper provided withperforations at these [sic] other end, and this cylinder comprisesseveral superposed compartments each containing an active substance, thesaid compartments being interconnected and each being closed off by thesaid temporary closure means.

Each compartment is formed of a cartridge provided with outer screwthreading at one of its ends and inner screw threading at its other end.

In this embodiment, the means for temporary closure of each compartmentcomprises a disk pierced with a central orifice, a stopper whose shapematches that of this central orifice and which is held on the saidcentral orifice by the biodegradable component supported by a ringapplied onto the said disk by the cartridge of the adjacent compartment.

In a fourth embodiment, the receptacle is formed of an envelope ofelongate shape made of leakproof material which is not biologicallydegradable, the receptacle comprising an opening at at least one of itsends and containing a matrix formed of a resin in which particles of ahigh-density material and particles of the said active substance aredistributed, the said opening being held closed by the saidbiodegradable component.

The envelope comprises an opening at each of its ends and the matrixcomprises a passage extending over the entire length of the said matrixand aligned in the axis of the said openings, each of these openingsbeing closed off by a stopper made of nonbiodegradable material and thesaid stoppers being linked together by the said biodegradable component.

In a fifth embodiment, the receptacle is formed of a cylindricalcontainer comprising two half-shells linked together at one of theirends by a portion forming a hinge and at its other end by the saidbiodegradable component in order to keep the container temporarilyclosed.

The half-shells are advantageously designed to contain a delayed-releaseform of an active principle of the type comprising a matrix in which anactive principle is dispersed and a central hollow being provided in thesaid matrix in order to allow a graded release of the active principlebased on the differences in migration path of the active principle fromthe matrix to the central hollow.

The biodegradable component advantageously consists of a thread or astrip made of a biologically degradable polymer.

Any biodegradable polymer material is suitable. Mention may be made ofpolyglycolic acid (PGA), polylactic acid (PLA) or a copolymer ofpolyglycolic acid and of polylactic acid (PLGA), poly(ε-caprolactone)(PCL), poly(p-dioxanone), polyanhydrides, polyorthoesters, etc.

In one preferred embodiment of the invention, the biodegradablecomponent consists of a surgical suture thread, in particular asingle-filament or braided surgical suture thread.

Threads of this type which may be suitable are, in particular,polyamides, such as those described in U.S. Pat. No. 5,068,220,polyglycolic acid polymers, for example the one sold under the brandname Vicryl®; a copolymer of glycolic acid and of lactic acid, forexample the one sold under the brand name Dexon®; a copolymer oftrimethyl carbonate and of glycolic acid, for example the one sold underthe brand name Maxon®; a poly(p-dioxanone), for example the one soldunder the brand name PDS II®, an ε-caprolactone/glycolic acid blockcopolymer, for example the one sold under the brand name Monocryl®. Thediameter of the thread or strip is variable and depends on the size ofthe device, the nature of the material used and the time after which itsdegradation is desired.

A person skilled in the art is capable of determining the thickness ofthis thread or strip, by means of routine calculations. Preferred suturethread sizes correspond to the numbers: 0, 1/0 and 2/0.

Closure of the strip or suture thread is ensured by maintaining tensionon the ends of the strip or thread, by any suitable means, in particularby means of a knot or any external device for holding together the freeends of the thread or strip, such as adhesive, wax, a non-degradablepolymer, a circlip, etc.

A bioresorbable screw made of a material which is resorbed byhydrolysis, such as a high molecular weight polymer of polylactic acidor polycaprolactone type, is also advantageously used.

A screw of this type is used in maxillofacial surgery and is sold underthe name Phusiline®.

The biologically active substance advantageously consists of a medicinalproduct, in particular an anthelmintic agent, a growth promoter, etc.,the device being intended in this case to be introduced into the stomachof a ruminant.

When the device is a flexible sachet, in particular, and when the suturethread has lost its mechanical properties, the release of the activesubstance can be facilitated by formulating the active principle in aneffervescent pharmaceutical form or by adding an effervescent mixturewith no pharmacological properties into the sachet along with thediffuser. In this case, the mixture can consist of citric acid andsodium bicarbonate, or other mixtures whose hydration produces a gas.

By dilating the flexible sachet, this gas facilitates the release of theactive substance into the surrounding biological medium.

In order to avoid regurgitation phenomena, the device according to theinvention, in particular in the form of the first embodiment of theinvention, can be inserted in a bag which is provided with perforationsor which allows easy diffusion of the active principle, or the sachet ofthe device will contain either a rolled-up sheet which, after unrolling,will prevent regurgitation of the device, or will be made more dense bythe addition of a component for increasing the density.

Advantageously, the device then comprises a flexible or deformablesachet containing a support sheet in which an active principle isdispersed, the said support sheet being designed so as to be able to bearranged positively, by deformation, in a first rolled-up form and totake a second form in the rumen, the device being held in the rumen byvirtue of this second form.

A subject of the invention is also a device as described for the firstembodiment of the invention, comprising a flexible or deformable sachetcontaining a support sheet of the abovementioned type, the sachet andthe support sheet being in a rolled-up form with the closure meanslocated inside the roll, and the assembly being held in this rolled-upform by a positive deformation means which can be rapidly eliminated inthe rumen.

The perforated sheet or sheet provided with perforations can also berolled up around the device and the assembly included in a bag asdescribed above.

Systems of this type in the form of a matrix capable of rolling up andunrolling once in the rumen of an animal are described in EP 334,516,U.S. Pat. No. 3,844,285 and EP 10,967.

The regurgitation phenomena can also be avoided by providing the deviceof the invention, in particular in the second, third and fourthembodiments of the invention, in an elongated cylindrical form providedwith a ballasting component.

A subject of the invention is also a system for distributing one or moreactive substances, which is intended to be used in a biological medium,in particular the rumen of an animal, this system comprising at leasttwo devices arranged one inside another, each container containing,optionally besides the said active substance, at least one other similarcontainer, or each container being contiguous with the others.

In a first embodiment of the multi-container system of the invention,the system comprises a first outer device as described above in relationto the first embodiment of the invention, preferably containing anactive substance and in turn comprising at least one other similardevice containing a biologically active substance, this substancepreferably being different from the one contained in the outer device orthe device(s) arranged in the outer device. This system thus allows therelease of biologically active substances of different nature, inparticular of the substances which are incompatible in terms of chemicaland/or physical stability or which are pharmacologically incompatible.

In a second embodiment of the multi-container system, the devices areorganized in a nesting arrangement. In other words, the system comprisesa first outer device containing, besides an active substance, a deviceof smaller size which contains, besides a second active substance, athird device smaller than the second device, and so on.

One or other of the systems described above can be designed so as toprovide a sequential release as a function of the pharmacological,chemical and physical properties of several different active principles.

The active substances can be of different nature, or of the same natureand of different dosages. It is thus possible to provide a system ofdevices arranged one inside another in a nesting manner, in which thecontainers for the respective devices contain the same active substance,but at increasing doses, in going from the outermost system to theinnermost system. In this manner, release of the biological substancewill be obtained over time, such that, when this is an anthelminticsubstance, the maximum dose will be released at a chosen moment, forexample at the end of the season in pasture, or alternatively therelease of active principles in different physical forms, for example aliquid active principle and another solid.

Nonlimiting examples of active principles with pharmacological activitywhich can be administered by means of a device and/or a system accordingto the invention are anthelmintic agents such as ivermectin, moranteltartrate, levamisole hydrochloride, oxfendazole, etc., trematicides, inparticular rafoxanide, antibiotics and vaccines.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in greater detail in the descriptionwhich follows, for which reference will be made to the attached figuresin which:

FIG. 1 represents an exploded perspective view of a first embodiment ofa device according to the invention representing a container and itsclosure means;

FIG. 2 represents a perspective view of the container according to thefirst embodiment of the invention, held closed by means of a clip;

FIG. 3 represents a variant of the mode of closure of the clip in thedevice according to the first embodiment of the invention;

FIG. 4 represents a system composed of several devices according to thefirst embodiment of the invention, arranged one inside another;

FIG. 5 represents a system composed of several devices according to thefirst embodiment of the invention, organized in a nesting arrangement;

FIG. 6 represents a perspective view of a second embodiment of a deviceaccording to the invention, in a form which is particularly suitable foradministration to a ruminant;

FIG. 7 represents an exploded perspective view of a device according tothe invention representing a container and its closure means;

FIG. 8 represents a longitudinal view of a third embodiment of a deviceaccording to the invention;

FIG. 9 represents an exploded perspective view of one part of the deviceaccording to the third embodiment;

FIG. 10 represents a biodegradable component in the form of abiodegradable screw;

FIG. 11 represents a view in longitudinal cross section of a fourthembodiment of a device according to the invention;

FIG. 12 represents a front view of a fifth embodiment of a deviceaccording to the invention, in the closed position;

FIG. 13 represents a front view of the device according to the fifthembodiment, in the open position.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The device 1 represented in FIG. 1 comprises a container 2 formed of aflexible leakproof sachet, three sides of which are welded, the fourthside 3 being held open.

The device also comprises a means for temporary closure of the open end3 of the sachet 2. In this embodiment, this closure means consists of aclip 4 comprising two arms 5 and 6 linked at one of their ends by alinking portion 4 a forming a hinge to hold the arms 5 and 6 of the clipin the open position in the absence of an external force.

Each arm 5 and 6 comprises longitudinal grooves 7 on its inner face.

A channel 8 extends over the outer faces 9 of the said arms.

The open end 3 of the flexible leakproof sachet 2 in which the activeprinciple, in this case a tablet 12, has been placed, is placed betweenthe open arms 5, 6 of the clip 4. These arms are then squeezed togetheras represented in FIG. 2, the grooves 7 interlocking, and held in thisconfiguration by means of a biodegradable suture thread 13 located inthe channel 8, the two ends of which are linked by means of a knot 14.

In this form, or after introduction into a perforated bag comprising anunrollable rolled-up sheet as described above, the device is introducedinto the rumen of a bovine in a known manner, with the aid of a pistolcommonly used for introducing boli into the digestive tract of aruminant. The device can also be rolled up on itself, as describedlater.

On contact with the gastric juice in the rumen, the biodegradable suturethread 13 degrades gradually until it is broken, promoted by the tensionexerted on the arms 5, 6 of the clip 4, at the desired moment of releaseof the active principle.

This tension exerted on the arms of the clip can also be increased byapplying a spring system, not represented, between the arms 5, 6 of theclip 4.

FIG. 3 represents a variant of the mode of fixing of the suture thread13 onto the arms 5, 6 of the clip 4. In this embodiment, the arms 5, 6each contain a hole 15. The biodegradable suture thread 13 is introducedinto these holes and its ends are linked by any means, in particular aknot.

Also as a variant, the arms of the clip can comprise a ring at theirend, in which case they are held together by means of a thread passingthrough the two rings, the ends of the thread being linked together by asuitable means, for example a knot.

The durations after which a device as described above releases theactive principle it contains will be given below. The threads used areall No. 2/0 threads, with a diameter of between 0.30 and 0.35 mm.

Nature of the No. 2/0 Time after which the suture thread substance isreleased Cat gut 7-10 days Chromium plated cat gut 21-28 days VicrylRapide 12 days Monocryl ® 21 days Vicryl ® 30 days PDS II 60 days

FIG. 4 represents a distribution system according to the inventioncomprising a first device 21 as described above, but with a closuremember 22 comprising two components which fit together in a leak-tightmanner, the two components being held together at each of their ends bymeans of a biodegradable thread 23 inserted into a channel 24, and thetwo ends of which are linked together by means of a biodegradable suturethread 23 as described above.

This first outer device comprises a flexible sachet 26 containing ananthelmintic active principle in the form of a tablet 27, as well as twoother identical devices 31, 32 which are smaller than the first outerdevice 21. The flexible sachet 33 of the device 31 comprises, forexample, a tablet 34 of an anthelmintic active principle and theflexible sachet 35 of the device 32, a gelatin capsule 36 containing avaccine the form of a lyophilizate, these two compounds showingpharmacological and possibly chemical incompatibility.

In another application, one of the devices can contain an acidicanthelmintic agent, for example levamisole hydrochloride, or a stronglybasic anthelmintic agent; another device in this case containing, forexample, an antibiotic which can be decomposed in acidic or stronglybasic medium.

In yet another application, one of the devices can contain an activeprinciple in the form of an anion, and another device can contain anactive principle in the form of a cation, so as to avoid the formationof a pair of ions.

By virtue of this embodiment, a simultaneous or staggered release can beobtained, depending on the nature and/or thickness of the biodegradablethreads 37, 38 on the devices 31, 32 during the summer months when theneed for an anthelmintic and trematicidal treatment will be greatest.

FIG. 5 represents another distribution system according to theinvention.

It comprises a first outer device 41, as described in FIG. 1 or 2, witha closure member 42 identical to those in the devices of FIG. 4. Theflexible sachet 43 of the device 41 contains a tablet 44 of ananthelmintic active principle at a first dose x₁ and another device 51,identical to the first but smaller than it in size. The flexible sachet52 of this second device 51 contains a tablet 53 of the sameanthelmintic active principle at a dose x₂, as well as a device 61identical to the first two and even smaller in size than the seconddevice 51, and the flexible sachet 62 of which contains a tablet 63 ofthe same active principle at a dose X₃.

The biodegradable threads 45, 55, 65 of the various “nesting” devices41, 51, 61 are preferably designed so as to release their respectiveactive principles in June, preferably at the end of June, July andAugust. The dose x₁ released in June is the lowest, the proliferation ofthe parasites being at its minimum, whereas the doses x₂ and X₃ arereleased at the end of July and the end of August and are suited to theincreasing amounts of worms found in pastures at these periods, and alsoto the weight increase of the animal.

When the medicinal product is an anthelmintic agent, the threads arepreferably designed to allow a first release of product one to twomonths after the animals have been placed in pasture (end of April-startof May) and the subsequent releases at intervals of 21 to 30 days,corresponding to the larval cycle.

FIG. 6 represents a device according to the invention in a form which isparticularly suitable for administration to a ruminant, in particular abovine.

This device 71 comprises a deformable sachet 72 containing a supportsheet 73 made of a water-insoluble polymer material, in which isdispersed a medicinal product. The support sheet is designed so as to beable to be positively arranged, by deformation, in a first rolled-upform.

As represented in FIG. 6, the dimensions of the support sheet 73 areslightly smaller than those of the deformable bag 72.

The device also comprises a clip 74 whose arms 75, and 76 grip the openend 77 of the deformable sachet 72 and are held together with the aid ofa suture thread 78 closed with a knot 79.

In a first stage, the support sheet 73 in which the active principle isdispersed is introduced into the sachet 72 and the open end of thesachet is closed using the clip 74; the assembly is then arranged bypositive deformation, for example by heating the support sheet to atemperature sufficient to soften the polymer but not to decompose themedicinal product, in the rolled-up form represented in FIG. 6, suchthat the clip 74 is inside the rolled-up form.

The assembly can be held in this position by an appropriate means, forexample one or two strips of adhesive paper 81, 82 bearing awater-soluble adhesive or one or two strips of a water-soluble polymer,in particular gelatin.

After oral administration, the strips of paper become detached or thegelatin dissolves and the device unrolls, leaving its first form underthe influence of the elasticity of the support sheet, and taking up asubstantially flat second form by virtue of which the device is retainedin the bovine's stomach.

The polymer support sheet in which the medicinal product is dispersedis, for example, of the type described in patent EP-010,967.

FIG. 7 represents a second embodiment of a distributor device accordingto the invention.

This device comprises a container denoted as a whole by the referencenumber 81 and formed of a rigid cup 82 of cylindrical shape, one end 82a of which is closed and the other end 82 b of which is open.

The cup 82 comprises screw threading 83 at its open end 82 b and on itsouter face.

Moreover, the container 81 also comprises a means for temporary closureof the open opening 82 b of the cup 82.

This temporary closure means consists of a thin disk 84 with an outsidediameter substantially equal to that of the cup 82 and pierced with acentral orifice 85, and preferably of frustoconical shape.

The top of the cone body delimited by the central orifice 85 faces intothe cup 82.

The temporary closure means also comprises a stopper 86 whose shapematches that of the central orifice 85 of the disk 84, i.e. offrustoconical shape.

The temporary closure means also comprises a ring 87 whose outsidediameter is substantially equal to the outside diameter of the cup 82.This ring 87 comprises a central bore 88 inside which is fixed thebiodegradable component 89 which holds the stopper 86 in the centralorifice 85 when the container 81 is closed, as will be seen later.

The biodegradable component 89 is preferably formed of a biodegradablethread whose ends are fixed to two diametrically opposite points of thebore 88 of the said ring 87.

Finally, the temporary closure means comprises a collar 90 provided withan orifice 91 at one of its ends and screw threading, not represented,on its inner face, which is intended to cooperate with the outer screwthreading 83 of the cup 82.

The assembly formed of the disk 84, the stopper 86 and the ring 87holding the said stopper 86 on the central orifice 85 is positioned onthe open end 82 b of the cup 82 and this assembly is held on the saidopen end 82 b by the collar 90 which is screwed onto the cup 82.

A tablet 92 containing an active principle is placed in the cup 82, onwhich are successively placed the disk 84, the stopper 86, the ring 87and the collar 90 which is screwed onto the cup 82.

The choice of the nature and size of the biodegradable thread 89 aredetermined by the duration after which the degradation of the saidthread 89 and the release of the active principle by means of the tablet92, are desired.

Following the movements of the medium in which it is placed, for examplethe animals movements, the stopper 86 then frees the orifice 85, intowhich the surrounding liquid medium penetrates, giving rise to therelease therein of the active principle contained in the container 81.

The various components constituting this container 81 are made of aplastic or metal material.

Now, with reference to FIGS. 8 and 9, a third embodiment of thedistributor device in accordance with the invention will be described.

As represented in FIG. 8, the container of the distributor device isformed of a cylinder denoted as a whole by the reference number 100,containing a ballasting component 101 at one of its ends and a stopper102 provided with perforations 103 at its other end.

The free end of the ballasting component 101 is preferably in afrustoconical shape.

The cylinder 100 comprises several compartments, A, B, . . . N,respectively, which can each contain an active substance. Thesecompartments A, B, . . . N, are interconnected and are each closed offby a temporary closure means. One compartment of the cylinder 100 willbe described with reference more particularly to FIG. 9, the othercompartments being identical.

Each compartment is formed of a cartridge 104 provided at one of itsends with outer screw threading 104 a and at its other end with innerscrew threading 104 b.

The cartridge 104 comprises on the inside, substantially in itsmid-section, an inner rim 104 c intended to receive the temporaryclosure means of the corresponding compartment.

This means for temporary closure of each compartment comprises a disk105 pierced with a central orifice 106, of frustoconical shape, and astopper 107 whose shape matches that of the central orifice 106.

The temporary closure means also comprises a ring 108 comprising abiodegradable thread 109 intended to hold the stopper 107 in the orifice106 of the corresponding disk 105.

The disk 105 and the ring 108 are held against the rim 104 c of thecorresponding cartridge 104 by the lower edge of the threaded end 104 aof the adjacent cartridge 104.

A sealing joint 110 and a collar 111 are placed between the ring 108 andthe lower edge of the threaded end 104 a of the corresponding cartridge104.

As represented in FIG. 8, the threaded end 104 a of the cartridge 104 ofthe lower compartment N is intended to be screwed into the ballastingcomponent 101 and the upper threaded end 104 b of the cartridge 104 ofthe upper compartment A is intended to receive the stopper 102.

The various components comprising the cylinder 100 of the distributingcontainer are preferably made of plastic or metal.

The perforations 103 in the lid 102 allow the passage of the biologicalliquid medium in which the release system is placed and theseperforations 103 are small enough not to allow the passage of fibres orother solid elements which might be in the surrounding medium and whichmight harm the release of the active substance contained in eachcompartment.

Advantageously, the upper compartment A of the device contains notablets containing an active principle, such that, where appropriate,the animal has the time to acquire a certain level of protectiveimmunity before the number of parasitic worms becomes too large.

The liquid biological medium penetrates into the first compartment A viathe perforations 103 and, at the end of the period envisaged, thisbiological medium degrades the biodegradable thread 109 of the saidfirst compartment A so as to result in the release of the stopper 107closing the orifice 106 which communicates with the second compartment Bof the device.

The biological liquid in the surrounding medium can then penetrate intothe next compartment B and bring about disintegration of the tablet 112located inside this compartment B and result in the release of theactive principle contained in this tablet 112 into the surroundingbiological medium.

The successive opening of each compartment can take place at regular orirregular intervals depending on the nature and thickness of thebiodegradable thread(s) 109.

Each compartment can contain the same active principle at identical ordifferent doses, for example progressively increasing doses, or cancontain active principles according to the desired pharmacologicalactivity or the desired pharmacokinetics.

Instead of the biodegradable thread 109, each compartment can be closedoff by a stopper in the form of a screw 113, as represented in FIG. 10.

FIG. 11 represents a fourth embodiment of the distributing deviceaccording to the invention.

In this embodiment, the container is formed of an elongate envelope 120made of leakproof material which is not biologically degradable andcomprises an opening at at least one of its ends.

The envelope 120 contains a matrix 121 whose shape matches that of thesaid envelope 120.

This matrix 121 is formed of a resin in which are distributed particlesof a material of high density and particles of the active substance.

The opening of the envelope 120 is held closed by means of abiodegradable component.

The envelope 120 preferably comprises an opening 122 at each of its endsand the matrix 120 preferably comprises a passage 123 extending alongthe entire length of the said matrix 121 and arranged in the axis of thesaid openings 122.

As represented in FIG. 11, each opening 122 is temporarily closed by astopper 124 comprising a first cylindrical part 124 a whose diameter isslightly larger than the diameter of the opening 122, and a secondcylindrical part 124 b whose diameter is slightly smaller than thediameter of the opening 122. The second part 124 b is designed to fitinto the corresponding opening 122 and close it off temporarily.

The stoppers 124 are held in place in the openings 122 by the tensionexerted by the biodegradable component, which, in this case, consists ofa thread 125 in the form of a loop.

This biodegradable thread 125 extends over the entire length of thehollow 123 and crosses the stoppers 124 at two different points, forminga rounded end 125 a which projects beyond each stopper 124 and isaccessible for degradation by the surrounding biological medium.

The biodegradable thread 125 is designed to be broken at one or both ofits rounded ends 125 a, after a predetermined time, under the action ofthe surrounding biological liquid medium. The tension exerted by thethread 125 is then released and the stoppers 124 are released from theopenings 122.

The biological liquid can then penetrate into the passage 123 made inthe matrix 121 and the particles of active principle can be released ata rate which is a function of their distance from the centrallongitudinal axis of the passage 123.

In this embodiment, the stoppers 124 are made, for example, of rubber orsilicone.

In one variant, not represented, of this embodiment, the biodegradablethread can form a loop around the outer contour of the envelope 120. Forthis, the biodegradable thread 123 links each stopper 124, passingthrough each one transversely.

In a second variant, not represented, of this embodiment, the envelope120 comprises at least one opening 122 which is temporarily closed offby a biodegradable screw 113 as represented in FIG. 10. In this case,the corresponding orifice 122 comprises inner screw threading.

FIGS. 12 and 13 represent a fifth embodiment of the distributing devicein accordance with the invention.

In this embodiment, the container is formed of a cylindrical envelope130 comprising two half-shells 131 and 132 respectively.

The separation plane delimited by the two half-shells 131 and 132extends along the longitudinal axis of the envelope 130.

The half-shells 131 and 132 are hinged at one of their ends by a portion133 forming a hinge and each comprise an eyelet 134 at the end oppositethe one comprising the portion 133.

The half-shells 131 and 132 are held in a closed position by means of abiodegradable thread 135 passing through the eyelets 134.

The envelope 130 contains a delay form, comprising a matrix in which islocated an active principle, the matrix being designed for sustainedrelease of the active principle.

Such a delay form can consist of the delay form 121 described inrelation to FIG. 11.

The devices and systems according to the invention can be used in therumen of ruminants as described above, in particular bovines, sheep andgoats.

They can also serve for other types of use in which a programmed releaseor a release delayed over time, into a biological medium, of a substancesuch as a medicinal agent, a pesticide, a protein, a peptide, an enzyme,a nutrient or genetic material is desired. The biological medium can bean aquatic environment such as a river, a pond, an aquarium or adrinking trough.

The devices and systems according to the invention also have healthcareapplications, in particular for the delayed release over time ofdisinfectants, bacteria, etc.

What is claimed is:
 1. A device for distributing an active substance inan animal by oral administration, comprising: plural dosages, eachdosage comprising of an active substance for an animal; a leakproofcontainer containing the dosage, the leakproof container comprising atleast one opening; and a closure means for temporary closure of each ofthe at least one opening of the leakproof container, the closure meansbeing held closed, and under tension, by at least one biodegradablecomponent comprising a thread or a strip, such that, after the componenthas biodegraded, the closure means completely frees the opening, theleakproof container further comprising a cylinder with a ballastingcomponent at one end and a perforated stopper at another end, thecylinder comprising plural superimposed compartments, each compartmentcomprising one of the plural dosages, the plural compartments beinginterconnected and each of the compartments being closed off by one ofthe closure means.
 2. A device according to claim 1, wherein, eachcompartment further comprising a cartridge provided with an outer screwthreading at one end and an inner screw threading an another end.
 3. Adevice according to claim 1, wherein, the closure means for each of thesuperimposed compartments comprises a disk pierced with a centralorifice, and a stopper whose shape matches that of the central orifice,the stopper being held on the central orifice by the biodegradablecomponent supported by a ring applied onto the disk by the cartridge ofan adjacent compartment.
 4. A device according to claim 1, wherein, theclosure means comprises a member formed of two components which areapplied one against the other.
 5. A device according to claim 1,wherein, the two components being held together by the biodegradablecomponent.
 6. A device for distributing an active substance in an animalby oral administration, comprising: plural dosages, each dosagecomprising of an active substance for an animal; a leakproof containercontaining the dosage, the leakproof container comprising at least oneopening; and a closure means for temporary closure of each of the atleast one opening of the leakproof container, the closure means beingheld closed, and under tension, by at least one biodegradable componentcomprising a thread or a strip, such that, after the component hasbiodegraded, the closure means completely frees the opening, theleakproof container further comprising a cylinder the cylindercomprising plural superimposed compartments, each compartment comprisingone of the plural dosages, the plural compartments being interconnectedand each of the compartments being closed off by one of the closuremeans.